Recent studies have confirmed that theophylline is probably the most effective bronchodilator for the treatment of asthma that can be administered parenterally and orally. Unfortunately, the therapeutic range for theophylline is fairly narrow and its toxic effects stem largely from its action on the central nervous system, cardiovascular system, and gastrointestinal tract. It has been suggested that these undesirable pharmacological activities as well as the bronchodilation effect are related to theophylline's ability to competitively inhibit phosphodiesterase (PDE), which is an enzyme that degrades cyclic AMP. Thus, it is desirable to discover selective inhibitors of cyclic AMP phosphodiesterase which possess a beneficial bronchodilation effect but lack most of the adverse reactions of theophylline.
This invention relates to the discovery that certain 5,6-disubstituted-benzothiophene-2-carboxylic acids are potent phosphodiesterase inhibitors and bronchodilators. 5,6-Dimethoxybenzothiophene-2-carboxylic acid was first prepared by Bew and Clemo, J. Chem. Soc., 1314 (1953) and later by Campaigne and Kreighbaum (J. Org. Chem., 26, 359 (1961)). See also Tetrahedron, 25 (14), 2781 (1969). In J. Org. Chem., 26, 1327 (1961), Campaigne teaches that certain amide derivatives were found to possess analgesic and diuretic activity. Campaigne also teaches 5,6-diethoxybenzothiophene-2-carboxylic acid (J. Org. Chem., 26, 1326 (1961)) although no pharmaceutical utility is disclosed.